Comparison of the interaction of doxorubicin, daunorubicin, idarubicin and idarubicinol with large unilamellar vesicles - Circular dichroism study
Comparison of the interaction of doxorubicin, daunorubicin, idarubicin and idarubicinol with large unilamellar vesicles - Circular dichroism study
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DOI：
10.1016/s0005-2736(97)00241-1
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发表时间：
1998-03-06
影响因子：
3.4
通讯作者：
Garnier-Suillerot, A
中科院分区：
文献类型：
--
作者：
Gallois, L;Fiallo, M;Garnier-Suillerot, A
阿霉素、柔红霉素和其他蒽环类抗生素是当今癌症化疗中使用的最重要的药物之一。药物与膜相互作用的细节对于理解它们在膜中被动扩散的动力学特别重要，这本身就是癌细胞多药耐药(MDR)的基础。蒽环类化合物是具有二羟基蒽醌环系的两亲性分子，在生理条件下是中性的。它们的亲油性依赖于取代基，氨基糖部分在质子化的氨基氮上带有正的静电电荷。阿霉素、柔红霉素、伊达比星和艾达比星(一种很容易在细胞内形成的代谢物)具有相同的氨基糖基-柔红胺，其pK(A)为8.4。因此，所有被研究的药物都将表现出与膜的非常相似的静电相互作用，而总体药物膜行为的主要差异将源于它们的疏水特性。圆二色谱(CD)被用来更精确地了解药物-膜系统的构象。使用由磷脂酰胆碱、磷脂酸和胆固醇组成的大单层囊泡(LUV)。蒽环类药物与LUV的相互作用依赖于每种药物中磷脂的摩尔比。当药物：PA的摩尔比较低时，这些相互作用也依赖于蒽环类药物的亲脂性。因此，阿霉素和柔红霉素都以单体形式与膜结合，可见光下CD信号为阳性。然而，阿霉素的亲脂性很低，它通过静电相互作用与LUV结合，二羟基蒽醌部分在水相中，而亲油性更强的柔红霉素不能仅通过静电相互作用结合，实际上只有疏水相互作用才能检测到。高度疏水的伊达比星在双层内形成一个相当复杂的实体，包括2-3个以右旋构象结合的伊达比星分子，一个胆固醇分子和磷脂酸分子(S)，因为在没有带负电荷的磷脂的情况下检测不到这种特殊的寡聚物种。伊达比星与伊达比星的不同之处在于，它不是C(13)=O，而是CH(13)-OH，与LUV的相互作用也明显不同。它在可见光中的CD信号变为负信号，并且不能检测到双层内分子的自结合。Cotton效应符号由正到负的变化可能源于C(6a)-C(7)-O(7)-C(1‘)二面角的变化。值得注意的是，与伊达比星相比，C(13)-OH基团更有利于在水溶液中形成二聚体物种，从而防止了LUV双层内的缔合。当每种药物的磷脂比例较高时，它们都以单体的形式嵌入到双层中。(C)1998年爱思唯尔科学公司。
Doxorubicin, daunorubicin and other anthracycline antibiotics constitute one of the most important groups of drugs used today in cancer chemotherapy. The details of the drug interactions with membranes are of particular importance in the understanding of their kinetics of passive diffusion through the membrane which is itself basic in the context of multidrug resistance (MDR) of cancer cells. Anthracyclines are amphiphilic molecules possessing dihydroxyanthraquinone ring system which is neutral under the physiological conditions. Their lipophilicity depends on the substituents, The amino sugar moiety bears the positive electrostatic charge localised at the protonated amino nitrogen. The four anthracyclines used in this study doxorubicin, daunorubicin, idarubicin and idarubicinol (an idarubicin metabolite readily formed inside the cells) have the same amino sugar moiety, daunosamine, with pK(a) of 8.4. Thus, all drugs studied will exhibit very similar electrostatic interactions with membranes, while the major differences in overall drug-membrane behaviour will result from their hydrophobic features. Circular dichroism (CD) spectroscopy was used to understand more precisely the conformational aspects of the drug-membrane systems. Large unilamellar vesicles (LUV) consisting of phosphatidylcholine, phosphatidic acid (PA) and cholesterol, were used. The anthracycline-LUV interactions depend on the molar ratio of phospholipids per drug. At low molar ratios drug:PA, these interactions depend also on the anthracycline lipophilicity. Thus, both doxorubicin and daunorubicin bind to membranes as monomers and their CD signal in the visible is positive. However, doxorubicin with its very low lipophilicity binds to the LUV through electrostatic interactions, with the dihydroxyanthraquinone moiety being in the aqueous phase, while daunorubicin, which is more lipophilic is unable to bind only through electrostatic interactions and actually the hydrophobic interactions are the only detected. The highly hydrophobic idarubicin, forms within the bilayer a rather complex entity involving 2-3 molecules of idarubicin associated in the right-handed conformation, one cholesterol molecule and also molecule(s) of phosphatidic acid, as this special oligomeric species is not detected in the absence of negatively-charged phospholipids. Idarubicinol differs from idarubicin with CH(13)-OH instead of C(13)=O and its interactions with LUV are distinctly different. Its CD signal in the visible becomes negative and no self associations of the molecule within the bilayer could be detected. The variation of the sign of the Cotton effect (positive to negative) may derive from the changes in the C(6a)-C(7)-O(7)-C(1') dihedral angle. It is noteworthy that C(13)-OH group, which strongly favours formation of the dimeric species in aqueous solutions when compared to idarubicin prevent association inside the LUV bilayer. At high ratios of phospholipids per drug all of them are embedded within the bilayer as monamer. (C) 1998 Elsevier Science B.V.